Chemical Stability, Solid State Stability and “Storage Duration” of drug substance are particularly important factors in the manufacture of a medicament. The form identification of drugs which can be convenient manufacture, preparation and applied to patients is very important. Ideal drug substances and a combination thereof can be stored effectively during the evaluation period, and there are no obvious changes in physical and chemical properties (e.g., chemical composition, density, water absorbing rate, solubility and dissolution rate, etc.) of the active constituent.
A known amorphous form drug substance cannot solve the above problems well. For instance, an amorphous form drug substance is difficult to be managed and prepared, its solubility is unreliable and the chemical and physical property is usually unstable.
Therefore, if Technology R&D Specialists find a stable crystalline form during the drug development process, many of the above problems can be resolved. In the preparation of commercially available and pharmaceutically acceptable pharmaceutical compositions, if possible, providing medication in crystalline and stable form is important. However, the targets describe herein are not always achieved. Actually, it is usually impossible to predict crystallization behaviors and results of compounds only based on the molecular structure, the useful results can be obtained need to do a great amount of experimental explorations.
Patent WO 2008/154817 discloses a series of compounds which are used for preventing, managing, treating or lessening the severity of viral diseases in a patient, especially hepatitis B infection or a disease caused by hepatitis B infection. Patent WO 2008/154817 discloses specific compound 4[R,S]-ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (formula (II)), and the compound of formula (II) simultaneously has the tautomer 6 [R,S]-ethyl 6-(2-bromo-4-fluorophenyl)-4-(morpholinomethyl)-2-(thiazol-2-yl)-1,6-dihydropyrimidine-5-carboxylate (formula (IIa)). The compound and the tautomer have higher transforming speed at ambient temperature, which exists as the structure of 4 [R,S]-ethyl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate at ambient temperature. Formulae (II) and (IIa) are as shown below:
